Congenital Eye Defects Research Articles

Chlorpyrifos and cypermethrin combination disrupts sonic hedgehog signaling and associated regulatory molecules, leading to congenital eye defects in chick embryos

Pesticides are reported to be teratogenic for non-target species. Our studies have unraveled the teratogenicity of 50 % Chlorpyrifos & 5 % Cypermethrin combination (Ci) in developing chick embryos. A sub-lethal dose of this combination when administered to chick embryos, caused several developmental anomalies, with defects in eye development being frequent. Eye development begins at an early embryonic stage, with Sonic hedgehog (Shh) serving as a crucial signaling molecule. Shh plays a pivotal role in the early development of multiple organs, including the eye, by interacting with Pax6 and other regulatory molecules to guide the proper patterning of the eye. Thus, we hypothesized that Ci administration may lead to alteration in Shh expression which subsequently hampers downstream signaling molecules potentially contributing to congenital eye defects. Morphological, anatomical, histological, transcriptional and protein level analyses at various stages (Days 1,2,4 and 10) were carried out to evaluate the hypothesis. The results revealed a remarkable alteration of key regulators in treated embryos compared to control, providing insights into plausible causative mechanisms underlying Ci-induced congenital eye defects.

The first review on prenatal drug exposure and ocular malformation occurrence.

Even though a non-negligible portion of congenital eye anomalies has a clear genetic origin, an etiology is not found for most patients. Prenatal medication exposure is recognized to be involved in fetal malformations and several medications are specifically known to alter eye morphogenesis during embryonic development leading to congenital eye defects. We explored and reviewed the role of medications described in the genesis of ocular malformations, a role that has been little evaluated and probably still underestimated especially since several studies have shown the wide exposure of pregnant women to medication. We present our results in two sections; the first describes medications reported to be associated with ocular malformations in humans; the second details medications responsible for ocular malformations in animal models. We have summarized these results in tables, providing a relevant tool for clinicians. As most of the associations between medication exposure and congenital eye defects are either old or single case reports, this study highlights the needs for high epidemiological vigilance, accurate clinical description as well as a combination of studies on human genetics and experimental studies. Since medication exposures are potentially modifiable risk factors for congenital anomalies, this represents an important opportunity to implement preventive measures.

A Fanca knockout mouse model reveals novel Fancd2 function

Fanconi anemia (FA) is a genetically and clinically heterogenous inherited disorder. Clinically, Fanca subtype patients exhibited milder phenotypes compared to Fancd2 subtypes. Increasing evidence suggests that Fancd2 perform independent functions, but the detailed mechanisms are not well characterized. In this study, we developed a Fanca KO mice model in C57BL/6 background with ATG region deletion, then performed a detailed FA phenotypes characterization and analysis with Fanca KO mice and Fancd2 KO mice in the same congenic background. We found that both the Fanca KO and Fancd2 KO cause severe FA phenotypes in mice. However, Fanca KO mice exhibited milder FA phenotypes comparing to Fancd2 KO mice. Fanca KO mice showed higher embryonic and postnatal survival rate, less congenital eye defects in early development. At adult stage, Fanca KO mice showed increased HSC number and reconstitution function. Furthermore, we did RNA-seq study and identified differential expression of Dlk1 and Dlk1 pathway genes in Fanca KO and Fancd2 KO embryonic cells and adult HSCs. Finally, we revealed that Fancd2 was expressed and physically interact with Dlk1 in Fanca KO cells. Collectively, our findings suggested that Fancd2 has distinct functions in the absence of Fanca.

Single amino acid variation in MAB21L1 is dominantly associated with congenital eye defects

BackgroundDiagnosis of a genetic disease and determination of the causative molecular lesion rely on the availability of the disease-associated pedigrees. Microphthalmia is a congenital eye defect due to an insufficiently...

Gestational folic acid deficiency alters embryonic eye development: Possible role of basement membrane proteins in eye malformations

ObjectivesFolic acid (FA) is crucial before and during early pregnancy. FA deficiency can occur because dietary FA intake is low in mothers at the time of conception. Likewise, various ocular pathologies are related to the alteration of extracellular matrices. The present study aimed to investigate the association between maternal FA deficiency and congenital eye defects. We also investigated whether maternal diet deficient in FA alters the expression of collagen IV and laminin-1 as a possible mechanism responsible for the appearance of ocular malformations. Both proteins are the main components of the basal lamina, and form an interlaced network that creates a relevant scaffold basement membrane. Basal laminae are involved in tissues maintenance and implicated in regulating many cellular processes. MethodsA total of 57 mouse embryos were classified into the following groups: Control group, (mothers were fed a standard rodent diet), and D2 and D8 groups (mothers were fed FA-deficient [FAD] diet for 2 or 8 wk, respectively). Female mice from group D2 were fed a FAD diet (0 mg/kg diet + 1% succinyl sulfathiazole used to block the synthesis of FA) for 2 wk from the day after mating until day 14.5 of gestation (E14.5). On the other hand, female mice from group D8 were fed a FAD diet for 8 wk (6 wk before conception and during the first 2 wk of pregnancy). For the data analysis, we first estimated the incidence of malformations in each group. Then, the statistical analysis was performed using IBM SPSS Statistics, version 25.0. Expression patterns of collagen IV and laminin-1 were examined with the immunohistochemical technique. ResultsOur results showed that mice born to FA-deficient mothers had several congenital eye abnormalities. Embryos from dams fed a short-term FAD diet were found to have many significant abnormalities in both anterior and posterior segments, as well as choroidal vessel abnormalities. However, embryos from dams fed a long-term FAD diet had a significantly higher incidence of eye defects. Finally, maternal FA deficiency increased the expression of both collagen IV and laminin-1. Likewise, changes in the spatial localization and organization of collagen IV were observed. ConclusionsA maternal FAD diet for a short-term period causes eye developmental defects and induces overexpression of both collagen IV and laminin-1. The malformations observed are probably related to alterations in the expression of basement membrane proteins.

Functional Role of the RNA-Binding Protein Rbm24a and Its Target sox2 in Microphthalmia.

Congenital eye defects represent a large class of disorders affecting roughly 21 million children worldwide. Microphthalmia and anophthalmia are relatively common congenital defects, with approximately 20% of human cases caused by mutations in SOX2. Recently, we identified the RNA-binding motif protein 24a (Rbm24a) which binds to and regulates sox2 in zebrafish and mice. Here we show that morpholino knockdown of rbm24a leads to microphthalmia and visual impairment. By utilizing sequential injections, we demonstrate that addition of exogenous sox2 RNA to rbm24a-deplete embryos is sufficient to suppress morphological and visual defects. This research demonstrates a critical role for understanding the post-transcriptional regulation of genes needed for development.

Modeling ocular lens disease in Xenopus.

Ocular lens clouding is termed as cataract, which depending on the onset, is classified as congenital or age-related. Developing new cataract treatments requires new models. Thus far, Xenopus embryos have not been evaluated as a system for studying cataract. We characterized the developmental process of lens formation in Xenopus laevis tailbuds and tadpoles, and we disrupted the orthologues of three mammalian cataract-linked genes in F0 by CRISPR/Cas9. We assessed the consequences of gene inactivation by combining external examination with histochemical analyses and functional vision assays. Inactivating the key metazoan eye development transcription factor gene pax6 produces a strong eye phenotype including an absence of eye tissue. Inactivating the genes for gap-junction protein and a nuclease, gja8 and dnase2b, produces lens defects that share several features of human cataracts, including impaired vision acuity, nuclei retention in lens fiber cells, and actin fibers disorganization. We tested the potential improvement of the visual acuity of gja8 crispant tadpoles upon treatment with the molecular chaperone 4-phenylbutyrate. Xenopus is a valuable model organism to understand the molecular pathology of congenital eye defects, including cataracts, and to screen molecules with a potential to prevent or reverse cataracts.

Abnormal retinal pigment epithelium melanogenesis as a major determinant for radiation-induced congenital eye defects

Recent studies highlighted a link between ionizing radiation exposure during neurulation and birth defects such as microphthalmos and anophthalmos. Because the mechanisms underlying these defects remain largely unexplored, we irradiated pregnant C57BL/6J mice (1.0 Gy, X-rays) at embryonic day (E)7.5, followed by histological and gene/protein expression analyses at defined days. Irradiation impaired embryonic development at E9 and we observed a delayed pigmentation of the retinal pigment epithelium (RPE) at E11. In addition, a reduced RNA expression and protein abundance of critical eye-development genes (e.g. Pax6 and Lhx2) was observed. Furthermore, a decreased expression of Mitf, Tyr and Tyrp1 supported the radiation-induced perturbation in RPE pigmentation. Finally, via immunostainings for proliferation (Ki67) and mitosis (phosphorylated histone 3), a decreased mitotic index was observed in the E18 retina after exposure at E7.5. Overall, we propose a plausible etiological model for radiation-induced eye-size defects, with RPE melanogenesis as a major determining factor.

Peroxidasin is a novel target of the redox-sensitive transcription factor Nrf2

Peroxidasin (PXDN) facilitates peroxidative reactions via utilisation of hydrogen peroxide (H2O2) and has been shown to crosslink collagen IV through sulfilimine bond formation in the presence of hypohalous acids. Aberrant PXDN expression has been associated with kidney fibrosis, cancer, congenital eye defects and various cardiovascular disorders. Since PXDN expression is modified by H2O2, we hypothesized that a major antioxidant response transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), may regulate PXDN expression. PXDN expression in response to H2O2 and the Nrf2-specific inducers, tert-butylhydroquinone (tBHQ) and sulforaphane (SFN), was determined by western blotting and immunofluorescence microscopy, in HeLa and HEK293 cells. Chromatin immunoprecipitation and luciferase reporter assays were used to investigate the regulation of PXDN by Nrf2. We observed elevated Nrf2 nuclear translocation and increased PXDN protein expression in response to H2O2, tBHQ and SFN, in both cell lines. We found that Nrf2 binds to and increases luciferase reporter gene expression from the PXDN promoter via a putative Nrf2-binding site. In summary, we show that PXDN is a novel target of the redox sensitive transcription factor Nrf2. This finding further highlights the role of PXDN in redox-related processes and compliments the currently understood pathophysiological functions of PXDN.

Embryonic Surface Ectoderm-specific Mitofusin 2 Conditional Knockout Induces Congenital Cataracts in Mice

Inherited mitochondrial mutations can result in mitochondrial dysfunction or stochastic oxidative damage. Cumulative mitochondrial damage is an important factor in age-related disorders, such as cataracts and macular degeneration. Mfn2 mediates the fusion of mitochondria and contribute to the dynamic balance between fusion and fission that determines mitochondria morphology. We report here that conditional loss of Mfn2 function in the head surface ectoderm leads to a range of congenital eye defects, including small, opacified lens and small eyeball in the most severe phenotypes. The Le-Cre transgenic mouse line and Mfn2 flox mouse line were used in this study to generate Mfn2 conditional knockout mice. Our study revealed Mfn2 gene function in lens development and addressed the relationship between the mitochondria and lens transparency. Conditional loss of Mfn2 affected lens epithelium cell proliferation, apoptosis and ultrastructure of mitochondria. We conclude that proper development of the lens and lens transparency depend on normal Mfn2 gene function.

Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis

Keratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovirus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.

Identification of congenital rubella syndrome in Sudan.

BackgroundEpidemiological data about congenital rubella syndrome (CRS) are scarce and rubella vaccine is not yet included in the childhood immunization schedule in Sudan. This study aimed to identify and describe CRS cases among Sudanese infants with congenital eye or heart defects.MethodsBetween February and September 2010, paired oral fluid and dried blood spot samples were collected from 98 infants aged up to 12 months. These infants were enrolled during their visits to five hospitals in Khartoum, Sudan. Clinical samples were screened for rubella IgM and for ≥ 6 months old infants also for IgG antibodies by ELISA. The oral fluid of IgM and/or IgG positive patients was tested for rubella RNA by reverse transcriptase PCR.ResultsOur findings revealed that two children (2.0%) were IgM positive and another five children (5.1%) were positive for IgG antibodies. None of the five infants of which enough oral fluid was available for RNA investigation was PCR positive.ConclusionsThis study documented the presence of CRS in Sudan and highlighted the importance of rubella vaccine introduction for preventing future CRS cases in the country.

Toward postnatal reversal of ocular congenital malformations

Aniridia is a panocular disorder that severely affects vision in early life. Most cases are caused by dominantly inherited mutations or deletions of the PAX6 gene, which encodes a transcription factor that is essential for the development of the eye and the central nervous system. In this issue of the JCI, Gregory-Evans and colleagues demonstrate that early postnatal topical administration of an ataluren-based formulation reverses congenital malformations in the postnatal mouse eye, providing evidence that manipulation of PAX6 after birth may lead to corrective tissue remodeling. These findings offer hope that ataluren administration could be a therapeutic paradigm applicable to some major congenital eye defects.

Targeted analysis of four breeds narrows equine Multiple Congenital Ocular Anomalies locus to 208 kilobases

The syndrome Multiple Congenital Ocular Anomalies (MCOA) is the collective name ascribed to heritable congenital eye defects in horses. Individuals homozygous for the disease allele (MCOA phenotype) have a wide range of eye anomalies, while heterozygous horses (Cyst phenotype) predominantly have cysts that originate from the temporal ciliary body, iris, and/or peripheral retina. MCOA syndrome is highly prevalent in the Rocky Mountain Horse but the disease is not limited to this breed. Affected horses most often have a Silver coat color; however, a pleiotropic link between these phenotypes is yet to be proven. Locating and possibly isolating these traits would provide invaluable knowledge to scientists and breeders. This would favor maintenance of a desirable coat color while addressing the health concerns of the affected breeds, and would also provide insight into the genetic basis of the disease. Identical-by-descent mapping was used to narrow the previous 4.6-Mb region to a 264-kb interval for the MCOA locus. One haplotype common to four breeds showed complete association to the disease (Cyst phenotype, n = 246; MCOA phenotype, n = 83). Candidate genes from the interval, SMARCC2 and IKZF4, were screened for polymorphisms and genotyped, and segregation analysis allowed the MCOA syndrome region to be shortened to 208 kb. This interval also harbors PMEL17, the gene causative for Silver coat color. However, by shortening the MCOA locus by a factor of 20, 176 other genes have been unlinked from the disease and only 15 genes remain.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-011-9325-7) contains supplementary material, which is available to authorized users.

Ocular abnormalities in mice lacking the immunoglobulin superfamily member Cdo

Vertebrate eye development requires a series of complex morphogenetic and inductive events to produce a lens vesicle centered within the bilayered optic cup and a posteriorly positioned optic stalk. Multiple congenital eye defects, including microphthalmia and coloboma, result from defects in early eye morphogenesis. Cdo is a multifunctional cell surface immunoglobulin superfamily member that interacts with and mediates signaling by cadherins and netrins to regulate myogenesis. In addition, Cdo plays an essential role in early forebrain development by functioning as coreceptor for sonic hedgehog. It is reported here that Cdo is expressed in a dynamic, but dorsally restricted, fashion during early eye development, and that mice lacking Cdo display multiple eye defects. Anomalies seen in Cdo(-/-) mice include coloboma (failure to close the optic fissure); failure to form a proper boundary between the retinal pigmented epithelium and optic stalk; defective lens formation, including failure to separate from the surface ectoderm; and microphthalmia. Consistent with this wide array of defects, developing eyes of Cdo(-/-) mice show altered expression of several regulators of dorsoventral eye patterning, including Pax6, Pax2, and Tbx5. Taken together, these findings show that Cdo is required for normal eye development and is required for normal expression of patterning genes in both the ventral and dorsal domains. The multiple eye development defects seen in Cdo(-/-) mice suggest that mutations in human Cdo could contribute to congenital eye anomalies, such as Jacobsen syndrome, which is frequently associated with ocular defects, including coloboma and Peters' anomaly.

Incidence of ocular congenital anomalies in a Nigerian Teaching Hospital

Objective : The aim of this study was to report the pattern and incidence of congenital eye defects among patients seen in a semi-urban academic tertiary referral institution. Methodology : We reviewed all consecutive new patients with congenital abnormality seen between January 1998 and December 2003 at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria Data was analyzed using simple descriptive statistics on SPSS statistical package version 10. Results : A total of 189 patients with congenital defects were seen during the study period, of which 31(16.4%) had congenital eye defects {male 16(51.6%), female 15 (48.4%)} with a male to female ratio of 1:1. Their ages at presentation ranged from 1 day to 23 years with mean age± SD at 1.6 years ±0.5 years. Congenital eye defects seen were congenital cataracts 6(19.4%), microphthalmia 5(16.1%), nasolacrimal duct obstruction 4(12.9%), congenital glaucoma 3(9.7%), lid coloboma 3(9.7%), congenital ptosis 2(6.5%), pseudo-proptosis 2(6.5%), and lid haemangioma 2(6.5%). Prevalence of blindness was 9.8%. Conclusion : Congenital eye defects constitute a significant cause of morbidity (16.4%) and blindness (1.6%) among cases of congenital defects seen in the teaching hospital. Keywords : congenital, eye defects Orient Journal of Medicine Vol. 17(3&4) 2005: 31-36

The genetic and molecular basis of congenital eye defects.

The mature eye is a complex organ that develops through a highly organized process during embryogenesis. Alterations in its genetic programming can lead to severe disorders that become apparent at birth or shortly afterwards; for example, one-half of the cases of blindness in children have a genetic cause. This review outlines the genetic basis of eye development, as determined by mutation analysis in patients and in model organisms. A better understanding of how this intricate organ develops at the genetic and cellular level is central to our understanding of the pathologies that afflict it.

Teratogen-induced eye defects mediated by p53-dependent apoptosis.

Many birth defects are believed to involve gene-environment interactions, although the mechanisms involved are poorly understood. Apoptosis is a common effect of many kinds of environmental stresses on the developing embryo; therefore, mechanisms of teratogenesis may be approached within the context of the cell death program. The p53 tumor suppressor gene encodes a transcription factor which functions as a critical regulator of apoptosis in response to environmental stress. To investigate the relationship between p53-dependent apoptosis and teratogenesis, we subjected day 8 mouse embryos with different p53 gene backgrounds to a genotoxic stress, 2-chloro-2'-deoxyadenosine. Treatment rapidly stimulated nuclear p53 accumulation and triggered apoptosis in some (head-fold) but not other (primitive heart) developing structures. Induced cell death was p53 gene-dose dependent, as shown by the intermediate sensitivity of 4-5 somite stage embryos bearing only a single effective p53 allele and the lack of sensitivity of p53-null mutants. Abnormal development was manifested as eye defects by day 11, particularly lens agenesis. Overall the incidences of these defects at term were 73.3% for p53 wild-type fetuses, 52.5% for heterozygous mutants, and 2.2% for p53-null mutants. Statistical analysis indicated that the interaction between teratogen and genotype was highly significant (P < or = 0.001) for cell death on day 8 and eye defects on day 17. We conclude that teratogen induction of p53-dependent apoptosis in the developing embryo is positively coupled to the determination of congenital eye defects.

Distal deletion of the short arm of chromosome 6

We report on a patient with deficiency of distal 6p and compare the clinical and cytogenetic findings in this child with those of three previously reported patients who had similar deletions. Distal del(6p) appears to be associated with a relatively non-specific phenotype, with the possible exception of unusual congenital eye findings. This apparent association of congenital eye defects with distal del(6p) was supported by comparison with patients having other deletions of chromosome 6, particularly those with ring chromosome 6.

Patterns of retinal projections to the lateral geniculate nucleus and superior colliculus of rats with induced unilateral congenital eye defects

Patterns of retinal projections to the lateral geniculate nucleus and superior colliculus of rats with induced unilateral congenital eye defects